This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The SHIV/female rhesus macaque model is being used to evaluate the toxicity and efficacy of 2 candidate vaginal microbicides, RC-101, an HIV co-receptor blocker, and CSIC, a non-nucleoside reverse transcriptase inhibitor. The SIV-HIV recombinant virus, RT-SHIV, carries the HIV-1 RT coding region. This virus is susceptible in vitro to both candidate drugs. This project will interact closely with the other projects 1-3 and the cores that will carry out the in vitro studies needed to validate RC-101 and CSIC for use in the monkey model. The aims of the study are: 1. To assess vaginal and systemic toxicity of CSIC and RC-101 in adult rhesus macaques. Vaginal colposcopy will assess inflammation associated with drugs in the silicone rings that will be specially made for use in macaques. Sera will be tested for absorption of drug(s) and vaginal washes will be used to assess release of drug into the vaginal vault. 2. To determine the minimal infectious dose for RT-SHIV by the vaginal route. Six macaques will be used to determine the minimal infectious dose of RT-SHIV by the vaginal route. 3. To test the efficacy of RC-101 as a vaginal microbicide against RT-SHIV. Twelve female rhesus macaques will be used to test prevention of transmission by vaginal silicone ring application containing RC-101 4. To test the efficacy of CSIC, a non-nucleoside RT inhibitor against vaginal challenge with RT-SHIV. Twelve female rhesus macaques will be used to test prevention of transmission by CSIC containing silicone rings. 5. To test the efficacy of the combination of CSIC and RC-101. The final plan is to deliver both drugs in the same ring formulation. The goal is to show that these 2 drugs can be used together and will afford better protection against HIV-1 vaginal infection than either could alone. Thus far animals have been requested for aim 1.